This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DE-104 Functional Restoration of Salivary Glands. Proper salivary gland function is critical for oral health. Radiation therapy for head and neck cancer often causes significant secondary side effects that impact normal salivary gland function, most commonly xerostomia. The ensuing salivary gland hypofunction results in significant morbidity, diminishes the effectiveness of anti-cancer therapies and decreases the quality of life for these patients. Current therapies are unable to permanently restore salivary function, which remains a major therapeutic challenge. The primary goal of our research is to elucidate the role of radiation-induced autophagy in salivary glands in response to irradiation. Secondarily, through the use of small molecule therapeutic approaches, we wish to investigate whether activation of autophagy leads to cytoprotection or exacerbation of radiation-induced injury to salivary tissues. Autophagy is a constitutive cellular catabolic degradation process whereby cellular proteins and organelles are engulfed, digested through the lysosomal machinery and recycled. Depending on the cellular context, autophagy can affect pro-survival or pro-death outcomes. The autophagy-related 5 gene, Atg5, has been established as an indispensable player in autophagy. We have generated Atg5f/f;Aqp5-Cre transgenic mice, in which the Aquaporin-5 (Aqp5)-driven Cre recombinase is targeted to impair autophagy by excising the floxed exon 3 of Atg5 specifically in salivary acinar cells. We propose to investigate the role of autophagy in influencing the fate of salivary acinar cells following radiation and to utilize the FDA approved autophagy activator rapamycin or autophagy inhibitor chloroquine in a restoration of salivary function model. Our central hypotheses are: 1) Appropriate activation of autophagy is important in the removal of damaged organelles/proteins within damaged acinar and ductal cells as well as whole cell corpses following irradiation, and 2) Timely and efficient removal of cell corpses following irradiation by autophagy will accelerate restoration of salivary function. The expected outcomes from these experiments will contribute substantially to our understanding on the role of autophagy in protecting salivary gland function against radiation-induced damage. In addition, they will provide a unique opportunity to evaluate the feasibility of autophagy-targeted therapies to restore salivary gland function in thousands of head and neck cancer patients that have completed anti-cancer therapies yet continue to suffer from the side effect of salivary gland hypofunction. This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DE-104 Functional Restoration of Salivary Glands. Proper salivary gland function is critical for oral health. Radiation therapy for head and neck cancer often causes significant secondary side effects that impact normal salivary gland function. This proposal will provide a unique opportunity to evaluate the feasibility of autophagy-targeted therapies to restore salivary gland function in thousands of head and neck cancer patients that have completed anti-cancer therapies yet continue to suffer from the side effect of salivary gland hypofunction.